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How Toxic is Nicotine?

This article originally appeared in the Newton blog on RealClearScience. You can read the original here.

Nicotine, the addictive ingredient in cigarettes, can be quite a lethal compound. It's widely recognized to be deadly at doses between 30 and 60 milligrams, making it more dangerous than both arsenic and cyanide. But thanks to some scientific sleuthing courtesy of a dedicated toxicologist, nicotine may have to surrender its infamous position.

Dealing with toxins by trade, Bernd Mayer at Karl-Franzens University in Austria was well acquainted with nicotine's standing, but also irked by the lack of evidence for it. So he took it upon himself to trace the estimate's source. At first, his quest stalled.

"Literature and Internet searches provided circular and often misleading references to databases or textbooks, which either simply stated the dose without reference or referred to another textbook and so on," he lamented. Even the Centers for Disease Control cited dubious sources, Mayer found.

Persistent, Mayer began screening German scientific literature published before World War II, and soon started noticing references to a compendium of intoxicants assembled by prominent German pharmacologist Rudolf Kobert in 1906. It was in the dusty pages of a chapter on nicotine that Mayer found his biggest clue yet:

"The lethal dose of pure nicotine is... difficult to determine," Kobert wrote, "because it easily decomposes a bit and, on the other hand, mostly contains more or less water; however, in accordance with the severe symptoms evoked in several experimenters by 0.002-0.004 g it is certainly not going to be higher than 0.06 g."

Mayer knew he was on the right track.

"It is beyond any doubt that this short, not particularly convincing paragraph represents the genuine origin of the lethal nicotine dose we still refer to more than 100 years later," he said. Clue in mind, Mayer further unraveled the mystery, uncovering the experiments Kobert referred to in his textbook.

Sometime in the 1850s, two German experimenters, known only as Dworzack and Heinrich, took it upon themselves to discover what would happen if they directly consumed nicotine. Here's what happened, as described by Austrian pharmacologist Carl Damian von Schroff in 1856:

"These authors felt a burning sensation in the mouth, scratchy throat, increased saliva excretion, followed by a feeling of warmness emanating from the stomach, which spread over the chest and from the head to the toes and fingertips. Afterwards the subjects became agitated, suffered from headache, dizziness, numbness, cloudy vision and hearing, light sensitivity, anxiety, dryness of the throat, coldness of the limbs, ructus [belch], flatulence, nausea, vomiting and rectal tenesmus. Respiration was accelerated and labored, pulse rate increased initially, and rose directly with the increasing dose; but later rose and fell erratically. After 45 min the experimenters lost consciousness. One of them suffered clonic seizures for 2 h, particularly of the respiratory muscles, also tremors of the limbs and shivering over the whole body."

The account is remarkably consistent with what we now know of severe nicotine poisoning, but it deviated from the facts in one key respect. By the self-experimenters' reports, this deleterious chain of symptoms was set in motion after they ingested a mere 4 milligrams of nicotine. For comparison, that's roughly equivalent to the amount absorbed after smoking just four cigarettes! That can't be right. With 43.8 million regular smokers in the United States, we should be seeing a terrifying outbreak of seizures and tremors. We're not. This shoddy account is obviously incorrect, yet it appears to be the sole basis for nicotine's estimated toxic dose!

Nicotine is, without a doubt, one murderous compound. When concentrated, it's corrosive to soft tissues, and targets the nervous system with frightening speed. But despite it's deadliness, common knowledge needs revision. Citing studies conducted in dogs, Mayer recommends updating nicotine's lethal dose to between 0.5 and 1 gram for the average person -- approximately 15 times the previous value -- but urges that new studies be completed to cement correct information into the scientific literature.